Tiacumicin compounds, especially Fidaxomicin, are indicated for the treatment of Clostridium difficile infections (CDI) also known as Clostridium difficile-associated disease (CDAD) and prevention of recurrences. CDI is a major burden on healthcare facilities worldwide (Wiegand P. N., Nathwani D., Wilcox M. H. et al. in J. Hosp Infect of 10 Apr. 2012; Ghantoji S. S., Sail, K. Lairson D. R. (2010) in J. Hosp. Infect. 74: 309-318).
These infections are normally caused by changes in the composition and function of the intestinal flora following the use of antimicrobials and are called antibiotic-associated diarrhea (AAD). Clostridium difficile infections (CDI) also known as C. difficile-associated disease (CDAD) refer to a wide spectrum of diarrheal illnesses caused by the toxins produced by this organism, including cases of severe colitis with or without the presence of pseudomembranes.
The occurrence of AAD varies greatly and is influenced by a number of factors, including nosocomial outbreaks, patterns of antimicrobial prescription, and individual susceptibility. It is estimated that 10% to 15% of all hospitalized patients treated with antibiotics will develop AAD. Most important, twice as many will become asymptomatic carriers. Risk factors include compromised immune status, advanced age, abdominal surgery, co morbidity, types and prolonged use of antibiotics, reduced gastric acid, and the length of hospitalization. For example, infection rates for Clostridium difficile are reported to be around 10% after 2 weeks of hospitalization but may reach 50% after 4 or more weeks (McFarland L V. Epidemiology, risk factors and treatments for antibiotic-associated diarrhea. Dig Dis 1998; 16:292-307)
All groups of antibiotics may cause AAD, but those with broad-spectrum coverage—in particular cephalosporins, fluoroquinolones, extended-coverage penicillins, and clindamycin—are the most common culprits (Wistrom J, Norrby S R, Myhre E, et al. Frequency of antibiotic-associated diarrhoea in 2462 antibiotic-treated hospitalized patients: a prospective study. J Antimicrob Chemother 2001; 47:43-50).
Treatment options are limited and are associated with high rates of recurrence.
Tiacumicin compounds are naturally occurring compounds with an antibiotic activity that can be obtained by cultivating various microorganisms belonging to the Actinoplanes family (especially the genus Dactylosporangium aurantiacum, subspecies hamdenensis) in a suitable nutrient medium at a suitable temperature and isolating the compounds having antibiotic activity against a variety of microorganisms (tiacumicins A-F; U.S. Pat. No. 4,918,174).
Especially tiacumicins B and C turned out to possess antibiotic activity against a number of Gram-positive bacteria in vitro including strains resistant to therapeutic antibiotics, used at the time.
U.S. Pat. No. 5,583,115 discloses dialkyltiacumicin compounds, which are derivatives of the above-mentioned tiacumicin compounds A-F, were found to have in vitro activity against a variety of bacterial pathogens and in particular against Clostridium species.
U.S. Pat. No. 5,767,096 discloses bromotiacumicin compounds, which are also derivatives of tiacumicin compounds A-F, which were found to have in vitro activity against some bacterial pathogens and in particular against Clostridium species.
From a chemical point of view the tiacumicins share an 18-membered macrocyclic ring, which is glycosidically attached to one or two optionally substituted sugar molecules (U.S. Pat. No. 4,918,174 and WO 2004/014295) as follows (formula I):

WO 2004/014295 describes substantially pure R-tiacumicins, obtained by submerged aerobic fermentation of Dactylosporangium aurantiacum hamdenensis. 
WO 2006/085838 discloses pharmaceutical compositions containing R-tiacumicins and especially R-tiacumicin B (also known under the name Fidaxomicin), which contains an R-hydroxy-group at C19, which shows surprisingly lower MIC (MIC stand for minimal inhibitory concentration) values when tested in vitro against Clostridium species than the optically pure S-isomer of tiacumicin B and other tiacumicin related compounds.
According to an in vitro BCS (Biopharmaceutics Classification System) study, fidaxomicin is a BCS Class IV compound (low solubility, low permeability). Upon oral administration fidaxomicin is poorly absorbed from the intestinal tract and is therefore associated with a low incidence of systemic side effects.
Tablets containing 200 mg fidaxomicin are commercially available in Europe (under the trademark Dificlir) and in the USA (under the trademark Dificin).
Fidaxomicin is indicated for the treatment of Clostridium difficile infections (CDI) also known as C. difficile-associated disease (CDAD) and prevention of recurrences.
In two Phase III randomised, double-blind, clinical trials, fidaxomicin demonstrated non-inferiority to vancomycin for initial clinical cure of CDI, but superiority in reduction of recurrence and sustained clinical response (Crook et al. (2012) in Clin. Infect. Dis. 55(Suppl 2): S93-103).
In phase III clinical trials the risk of fidaxomicin or vancomycin treatment failure doubled for each treatment day less than 10 days (T. Louie et al. Poster presented at 22nd European Congress of Clinical Microbiology & Infectious Diseases, March 31-Apr. 3, 2012, London). The relatively low impact of fidaxomicin on gut microflora may allow better recovery of bacteria during prolonged treatment periods, so reducing risk of CDI recurrence (T. J. Louie et al. (2012) in Clin. Infect. Dis. 55(S2) S132-142; Tannock in Microbiology (2010), 156, 3354-3359 (Phase II trials)).
The management of Clostridium difficile infections (CDI), thus, is complicated by high recurrence rates with over 50% of second episodes experiencing a recurrence (RCDI=recurrence of Clostridium difficile infections). Guidelines recommend managing multiple recurrences with a vancomycin taper. No clear recommendation is available for patients failing this approach. In a recent case series report (Soriano et al in Exp Rev Antiinf Ther 2013; 11:767-776), patients with multiple RCDI that were refractory to vancomycin taper therapy were given either fidaxomicin 200 mg BID for 10 days (FID-TX), or a repeat of CDI treatment followed by either a 10-day fidaxomicin regimen as a chaser (FID-CH), or a taper as 200 mg daily for 7 days, followed by 200 mg QOD for 7-26 days (FID-TP). Demographic information, CDI history, treatment outcomes, and symptom-free interval (SFI) were collected from patient records. Treatment success was considered if symptoms resolved by the end of therapy and no additional antibiotic was needed. RCDI (stand for recurrence of CDI) was defined by the onset of CDI symptoms following successful treatment for a previous episode. 14 patients received 18 courses of fidaxomicin for RCDI (mean age of 60, mean of 4.6 previous CDI episodes, mean of 2.3 previous vancomycin taper courses). All 18 courses resulted in treatment success (3 courses as FID-TX, 8 as FID-CH, and 7 as FID-TP). Of 3 FID-TX courses, there were 2 RCDI episodes (66%). When excluding RCDI due to antimicrobial exposure, there were 2 RCDI (25%) observed after the 8 FID-CH courses and no RCDI following the 7 FID-TP courses. The average SFI following a vancomycin taper was 37 days. The average SFI following FID-TX, FID-CH, and FID-TP was 73, 240, and 150 days, respectively. Patients with RCDI that failed multiple vancomycin tapers had symptom resolution following fidaxomicin therapy. All 3 regimens provided a greater SFI compared to a vancomycin taper. No patient experienced RCDI following FID-TP. FID-CH had the longest SFI, yet follow-up time with FID-TP was shorter given more recent adoption of this regimen. These results suggest the utility of using fidaxomicin to treat RCDI. (M. M. Soriano et al. Abstract 42591; presentation No. 1410; IDWeek, 5 Oct. 2013).
The currently recommended treatment regimen for adults and elderly people (65 years and older) is 200 mg administered twice daily (q12h) for 10 days.
A couple of dosage regimens were already tested for their activity in an in-vitro gut model such as the effectiveness of long (Model A: 200 mg BID during 20 days) versus short pulsed (Model B: 200 mg BID during 5 days, rest during 5 days and 5 days 200 mg BID) course fidaxomicin using a validated CDI model was investigated. Results are available for this model (C. H. Chilton et al. (2013) in J. Antimicrobial Chemotherapy Advance Access September 2013 and C. H. Chilton et al., abstract 23rd European Congress of Clinical microbiology & Infectious Disease, Apr. 27-30, 2013, Berlin).
Various Fidaxomicin dosing regimens were tested in an in vitro human gut model simulating CDI or CDAD. However it is unknown whether or not these dosing regimens will be effective if administered to patients as required by the present invention (C. H. Chilton et al (2014) in J. Antimicrobial Chemotherapy, 70:2598-2607 and C. H. Chilton (14 May 2014), poster presentation P0797)
In addition a comparison between two other models being model A: 200 mg Fidaxomicin BID for 5 days, followed by five days rest then again 200 mg Fidaxomicin once daily for further 10 days was compared with a model B providing 200 mg Fidaxomicin BID for 5 days followed by a single 200 mg Fidaxomicin dose every other day (Poster P0797 presented during poster session on 11 May 2014 during ECCMID congress in Barcelona).
None of the above cited dosage regimens have solved the issue of the high recurrence of CDI or CDAD. In the present invention recurrence is defined as a reappearance of >3 diarrheal stools per 24-hour period within 30 days of end of treatment (EOT), the presence of Clostridium difficile toxins A or B, or both, in stool and the need for re-treatment for CDI.
There are various indicators of CDI or CDAD available if tested positive alone or in combination to diagnose Clostridium difficile infections. Suitable indicators are for example the consistency of stools, the frequency of diarrhea, the presence of Clostridium difficile toxin A (TcdA) or toxin B (TcdB toxin), the presence of the Clostridium difficile toxin A gene (tcdA) or B gene (tcdB) and the presence of the Clostridium difficile surface antigen (GDH=glutamate dehydrogenase).
An accepted model to those skilled in the art is the Bristol Stool form scale as published by S. J. Lewis et al. In Scandinavian Journal of Gastroenterology, 1997, Vol. 32, No. 9, pages 920-924. In table 1 of this publication the seven types of the Bristol stool form scale are defined wherein type 7 is a watery stool and type 1 are separate hard lumps.
Bristol Stool Form ScaleType 1Separate hard lumps, like nuts.Type 2Sausage-shaped but lumpyType 3Like a sausage or snake but with cracks on its surfaceType 4Like a sausage or snake, smooth and softType 5Soft blobs with clear-cut edges.Type 6Fluffy pieces with ragged edges, a mushy stool.Type 7Watery, so solid pieces.
It is very important to apply to the patient the correct dosage regimen to achieve the therapeutic objective. Emphasis has to be placed on the route of administration, galenic formulation, unit dose, frequency of administration, loading dose and length of treatment. However there remains a need to provide a flexible dosage regimen which is adaptable depending on the change of reduction of certain indicators of CDI or CDAD or certain gut microflora indicators to secure best possible treatment for each patient and for reducing the recurrence of CDI or CDAD in said patient after the end of the treatment to a minimum level.